Thousands of pharmaceutical compounds are tested every year for pharmacokinetic properties and potential toxicity prior to clinical use. A major part of these tests is performed by administering a pharmaceutical compound to an animal and by assessing pharmacokinetic properties and/or toxicity at various points in time. These studies are, however, severely limited by the fact that the vast majority of pharmaceutical compounds elicit an immune response. Such an immune response is usually rapid, occurring within days or weeks, thereby drastically reducing the period of time during which an animal can be observed for evaluating pharmacokinetic properties and possible toxicity of pharmaceutical compounds. Obviously, the immune response also precludes any re-administration of pharmaceutical compounds.
The nature of an immune response can vary, from the elicitation of antibodies to the development of a cellular response, depending on the physicochemical properties of the antigen, the genetic background of the animal, the route, the doses and the frequency of administration. However, such immune response depends on antigen recognition by lymphocytes and activation of these cells, which belong to the CD4+ subset. Once activated, CD4+ T cells dictate the form and the fate of the response at multiple levels, including, yet not limited, activation of innate immunity, activation of B cells to mature and produce specific antibodies, enhancement of the capacity of antigen-presenting cells to activate CD8+ T cells, recruitment and activation of naïve CD4+ T cells and activation of cell immunity such as delayed type response, as observed with chemicals.
Considering the central role of CD4+ T cells in all these processes, a method by which it would become feasible to specifically prevent and/or suppress their activation would provide a highly specific state of immune tolerance to the pharmaceutical compound under evaluation (protein or non-protein organic compound).
Patent application WO2008017517 describes class II-restricted epitopes to which an oxidoreductase motif is added within residues flanking the amino acid sequence which fits into the class II major histocompatibility complex (MHC) cleft. Inclusion of an oxidoreductase motif converts an effector CD4+ T cell into a potent cytolytic cell, inducing apoptosis of the antigen-presenting cell with which a synapse has been formed, thereby preventing activation of effector cells of adaptive immunity. This concept is further elaborated for soluble allofactors (WO2009101206), intracellular pathogens (WO2009101208) and tumor associated antigens (WO2009101205).
WO2012069568 patent application describes CD1d-restricted T cell peptide epitopes to which an oxidoreductase motif is added within residues of the flanking sequence. Such peptide converts NKT cells into strong cytolytic cells eliminating the antigen-presenting cell with which a synapse is formed, thereby preventing activation of effector cells of innate immunity.
The above publications describe methods of prevention wherein healthy animals are treated with a peptide with redox motif and epitope of a pathogen, allergen, or autoantigen and are subsequently challenged with the disease causing agent.
The above publications describe methods of treatment wherein diseased animals (or models for such disease) are treated with a peptide with redox motif and an epitope of a therapeutic protein to prevent a subsequent immune response to this therapeutic protein.